EP1012167A1 - BASIC SALTS OF N- N-(3,3-DIMETHYLBUTYL)-L-$g(a)-ASPARTYL]-L-PHE NYLALANINE 1-METHYL ESTER - Google Patents
BASIC SALTS OF N- N-(3,3-DIMETHYLBUTYL)-L-$g(a)-ASPARTYL]-L-PHE NYLALANINE 1-METHYL ESTERInfo
- Publication number
- EP1012167A1 EP1012167A1 EP98946026A EP98946026A EP1012167A1 EP 1012167 A1 EP1012167 A1 EP 1012167A1 EP 98946026 A EP98946026 A EP 98946026A EP 98946026 A EP98946026 A EP 98946026A EP 1012167 A1 EP1012167 A1 EP 1012167A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aspartyl
- dimethylbutyl
- methyl ester
- basic salts
- phenylalanme
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
- A23L27/31—Artificial sweetening agents containing amino acids, nucleotides, peptides or derivatives
- A23L27/32—Artificial sweetening agents containing amino acids, nucleotides, peptides or derivatives containing dipeptides or derivatives
Definitions
- This invention relates to novel sweeteners.
- the invention relates to basic salts of the N-alkylated aspartame derivative,
- the invention also relates to a liquid low calorie sweetener containing such basic salts.
- N-substituted derivatives of aspartame such as disclosed in U.S. Patent No. 5,480,668, are useful as sweetening agents.
- the N-alkylated aspartame derivative N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester
- N-[N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester is known as an extremely potent sweetening agent since its sweetening potency, on a weight basis, has been reported to be at least 50 times that of aspartame and about 10,000 times that of sucrose .
- sweetening agents are often employed m aqueous solutions and beverages, it is important that they have an acceptable dissolution rate and an effective level of solubility to be commercially practicable.
- U.S. Patent No. 4,031,258 describes certain inorganic salts of dipeptide sweeteners that provide improved dissolution and solubility. N- [N- (3 , 3 -dimethylbutyl) - L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester, however, is not disclosed or suggested.
- N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ - aspartyl] -L-phenylalanme 1-methyl ester and aspartame differ m that, m N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ - aspartyl] -L-phenylalanme 1-methyl ester, a bulky neohexyl substituent is present on the amme nitrogen.
- N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1- methyl ester is 80°C, while that of aspartame is 248°C.
- N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester has much higher solubility m organic solvents than aspartame, and a much lower solubility in water.
- N-[N-(3,3- dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester has a higher stability than aspartame under some pH conditions, as described in U.S. Patent No. 5,480,688.
- the pronounced difference m sweetness between the two compounds is further evidence of their chemical dissimilarity.
- a primary ammo group such as the one on aspartame (pKa 7.7) generally has a different pKa than those from a secondary ammo group such as the one on N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ - aspartyl] -L-phenylalanme 1-methyl ester (pKa 8.1).
- pKa's of an ammo acid are known to have a profound impact on food applications (Labuza, T.P. and Basisier, M.W., 1992, "Physical Chemistry of
- N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester is a highly potent sweetener, it is sparingly soluble in water and can give rise to dusting problems. Therefore, there is a need for N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] - L-phenylalanme 1-methyl ester derivatives that have good dissolution and solubility properties in aqueous systems, and avoid dusting problems often encountered with fine powders.
- This invention relates to dipeptide sweeteners that are basic salts of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] - L-phenylalanme 1-methyl ester possessing good dissolution and solubility properties m aqueous systems.
- the basic salts of N-[N-(3,3- dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester of this invention are represented by the formula.
- X m+ is selected from the group consisting of
- the invention is also related to a liquid low calorie sweetener containing the basic salts of this invention.
- the figure is a graph comparing the aqueous dissolution of N- [N- (3, 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester at a target concentration of 0.05% by weight with equivalent neotame concentrations, i.e. the concentration of the neotame delivered in each case is the same, of the sodium and potassium salts of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ - aspartyl] -L-phenylalanine 1-methyl ester.
- This invention is directed to basic salts of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester, i.e., basic salts of neotame.
- U.S. Patent No. 5,480,668, U.S. Patent No. 5,510,508 and U.S. Patent No. 5,728,862 which describe the preparation of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] - L-phenylalanme 1-methyl ester are incorporated by reference herein as if fully set forth.
- the starting material may be readily prepared by one of ordinary skill m the art without undue experimentation.
- the basic salts of this invention may be prepared by adding N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester to a solvent or a mixture of solvents.
- exemplary solvents may include water, acetone, methanol , ethanol , acetonit ⁇ le, tetrahydrofuran and the like.
- N-[N-(3,3- dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester need not be completely soluble m the solvent . Thereafter, an equivalent amount of base is added to the solution and stirred for a period of time to achieve formation of the basic salt.
- N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester and the base may not be critical.
- the salt may be recovered by freeze drying or spray drying the resulting solution.
- Basic salts of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester prepared under these conditions do not show any racemization. However, addition of excess of base (more than 1 equivalent) does cause hydrolysis/racemization.
- the bases employed in the preparation of the basic salts of this invention are typically selected from compounds that have a pKa effectively higher than the pKa of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester to result in the formation of the desired salt.
- Such compounds include, for example, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, magnesium hydroxide, aluminum hydroxide, calcium hydroxide, ferric oxide, ferrous oxide, ammonium hydroxide, ammonium acetate, ammonium carbonate, zinc carbonate or z nc hydroxide.
- X ra+ is a physiologically acceptable cation selected from the group consisting of Na + , K + , Al 3+ , Fe 2+ , Fe 3+ , Ca 2+ , Mg + , NH 4 + and Zn 2+ .
- These ions can be used alone or m combination.
- the basic salts of this invention may also include a physiologically counter anion Q s .
- Such counter ions include, for example, OH , (OH) 2 2 , CH 3 C0 2 , Cl , S0 4 2 , P0 4 3 , O 2 or 0 2 4 .
- Particularly preferred basic salts of this invention include the sodium, potassium, magnesium, aluminum, calcium, ferric, ferrous, ammonium hydroxide and zinc salts of N- [N- (3 , 3 -dimethylbutyl) -1-L- ⁇ -aspartyl] -L- phenylalanme 1-methyl ester.
- the basic salts of this invention provide a number of improved properties over those of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester.
- the aqueous solubility is increased and the dissolution rate of the composition is greatly improved.
- These basic salts of neotame are sweet m taste.
- the basic salts of N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanme 1-methyl ester will be particularly useful m beverage systems, particularly since additional methods or mechanical preparations are diminished or not necessary to provide for quick dissolution such as desired in a table top sweetener.
- the basic salts of this invention may be admixed with known bulking agents to prepare tablets, powdered and granular sweeteners using methods well known to those skilled in the art.
- Another advantage of the basic salts of this invention is that they do not exhibit the dusting problems associated with N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanine 1-methyl ester.
- the basic salts may also be used to prepare a liquid, low-calorie sweetener by dissolving a high concentration of the basic salt of this invention in an aqueous or alcoholic system, e.g., water, propylene glycol, a water/propylene glycol mixture, ethanol or a water/ethanol mixture.
- a liquid, low-calorie sweetener may find utility in such foodstuffs as gelatin desserts, fruit flavored beverages, cereal, cake mixes, fruit juices, syrups, salad dressings, pet foods, carbonated soft drinks, table top sweeteners and the like.
- Such utilities are not restrictive since other applications may include cough medicines, tonics and the like.
- liquid table top sweetener as a replacement for sucrose and other known sweeteners.
- the liquid low calorie sweetener generally will contain up to about 40% by weight of the basic salt of N- [N- (3, 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanine 1-methyl ester, the concentration depending, of course, on the desired end use.
- Example 1 is intended as an illustration of certain preferred embodiments of the invention, and no limitation of the invention is implied.
- Example 1 is intended as an illustration of certain preferred embodiments of the invention, and no limitation of the invention is implied.
- N- [N- (3 , 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L-phenylalanine 1-methyl ester (0.05 - 0.1 g) was dissolved in water (100 mL) . The compound completely dissolved in 5-7 minutes (visual observation). The dissolution of 1.0 g of N- [N- (3, 3 -dimethylbutyl) -L- ⁇ -aspartyl] -L- phenylalanine 1-methyl ester in 100 mL of water required approximately 45 minutes.
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Abstract
Dipeptide sweeteners are disclosed that are basic salts of N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester represented by formula (I) wherein Xm+ is selected from the group consisting of Na?+, K+, Al3+, Fe2+, Fe3+, Ca2+, Mg2+, NH¿4?+ and Zn2+; Qs-¿ is absent or a physiologically acceptable counter anion; and m-s=n. Also disclosed is a liquid low-calorie sweetener containing such basic salts.
Description
TITLE
BASIC SALTS OF N- [N- (3 , 3 -DIMETHYLBUTYL) - L-α-ASPARTYL] -L-PHENYLALANINE 1-METHYL ESTER
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to novel sweeteners. In particular, the invention relates to basic salts of the N-alkylated aspartame derivative,
N- [N- (3,3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester, i.e., neotame. The invention also relates to a liquid low calorie sweetener containing such basic salts.
Related Background Art
It is known that various N-substituted derivatives of aspartame, such as disclosed in U.S. Patent No. 5,480,668, are useful as sweetening agents. In particular, the N-alkylated aspartame derivative, N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester, is known as an extremely potent sweetening agent since its sweetening potency, on a weight basis, has been reported to be at least 50 times
that of aspartame and about 10,000 times that of sucrose .
Since sweetening agents are often employed m aqueous solutions and beverages, it is important that they have an acceptable dissolution rate and an effective level of solubility to be commercially practicable. U.S. Patent No. 4,031,258 describes certain inorganic salts of dipeptide sweeteners that provide improved dissolution and solubility. N- [N- (3 , 3 -dimethylbutyl) - L-α-aspartyl] -L-phenylalanme 1-methyl ester, however, is not disclosed or suggested.
It is known that the physical properties, as well as the stability of aspartame and other peptides can be modified by conversion to their salts. This is disclosed, for example, U.S. Patent Nos . 4,031,258 and 4,153,737. U.S. Patent No. 4,153,737 also describes concentrated liquid low calorie sweetener.
Structurally, however, N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanme 1-methyl ester and aspartame differ m that, m N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanme 1-methyl ester, a bulky neohexyl substituent is present on the amme nitrogen.
Aspartame Neotame
This structural difference results in dramatic differences in the physical and chemical properties of these compounds. For example, the melting point of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-
methyl ester is 80°C, while that of aspartame is 248°C. In addition, N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanme 1-methyl ester has much higher solubility m organic solvents than aspartame, and a much lower solubility in water. It is also known that N-[N-(3,3- dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester has a higher stability than aspartame under some pH conditions, as described in U.S. Patent No. 5,480,688. The pronounced difference m sweetness between the two compounds is further evidence of their chemical dissimilarity.
Moreover, it is also known that a primary ammo group such as the one on aspartame (pKa 7.7) generally has a different pKa than those from a secondary ammo group such as the one on N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanme 1-methyl ester (pKa 8.1). Moreover, the pKa's of an ammo acid are known to have a profound impact on food applications (Labuza, T.P. and Basisier, M.W., 1992, "Physical Chemistry of
Foods", H.G. Schwartzber and R.W. Hartel (Eds.), Marcel Dekker, Inc., New York) . It is also well known that a secondary amme group can not form Schiff base type compounds with carbonyl compounds while a primary amme may. Furthermore, N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanme 1-methyl ester exhibits physiologically different behavior than aspartame as exemplified by the dramatic difference m sweetness. These differences are clearly indicative that the characteristics and properties of one can not be said to suggest those of the other.
While N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanme 1-methyl ester is a highly potent sweetener, it is sparingly soluble in water and can give rise to dusting problems. Therefore, there is a need for N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -
L-phenylalanme 1-methyl ester derivatives that have good dissolution and solubility properties in aqueous systems, and avoid dusting problems often encountered with fine powders.
SUMMARY OF THE INVENTION
This invention relates to dipeptide sweeteners that are basic salts of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] - L-phenylalanme 1-methyl ester possessing good dissolution and solubility properties m aqueous systems. In particular, the basic salts of N-[N-(3,3- dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester of this invention are represented by the formula.
wherein Xm+ is selected from the group consisting of
Na\ K\ Al3 Fe Fe3+, Ca2\ Mg2+, NH4 + and Zn2+, Qs is absent or a physiologically acceptable counter anion, and m-s=n (when Q is absent s is zero) . Preferably n is 1, 2 or 3. The invention is also related to a liquid low calorie sweetener containing the basic salts of this invention.
BRIEF DESCRIPTION OF THE DRAWING
The figure is a graph comparing the aqueous dissolution of N- [N- (3, 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanme 1-methyl ester at a target concentration of 0.05% by weight with equivalent neotame concentrations, i.e. the concentration of the neotame delivered in each case is the same, of the sodium and potassium salts of N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanine 1-methyl ester.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to basic salts of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester, i.e., basic salts of neotame. U.S. Patent No. 5,480,668, U.S. Patent No. 5,510,508 and U.S. Patent No. 5,728,862, which describe the preparation of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] - L-phenylalanme 1-methyl ester are incorporated by reference herein as if fully set forth. Thus, the starting material may be readily prepared by one of ordinary skill m the art without undue experimentation.
The basic salts of this invention may be prepared by adding N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanme 1-methyl ester to a solvent or a mixture of solvents. Exemplary solvents may include water, acetone, methanol , ethanol , acetonitπle, tetrahydrofuran and the like. N-[N-(3,3- dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester need not be completely soluble m the solvent . Thereafter, an equivalent amount of base is added to the solution and stirred for a period of time to achieve formation of the basic salt. It will be obvious to one skilled in the art that the order of addition of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanme 1-methyl ester and the base may not be critical. The salt may be recovered by freeze drying or spray drying the resulting solution. Basic salts of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester prepared under these conditions do not show any racemization. However, addition of excess of base (more than 1 equivalent) does cause hydrolysis/racemization.
The bases employed in the preparation of the basic salts of this invention are typically selected from compounds that have a pKa effectively higher than the pKa of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanme 1-methyl ester to result in the formation of the desired salt. Such compounds include, for example, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, magnesium hydroxide, aluminum hydroxide, calcium hydroxide, ferric oxide, ferrous oxide, ammonium hydroxide, ammonium acetate, ammonium carbonate, zinc carbonate or z nc hydroxide. As such, Xra+ is a physiologically acceptable cation selected from the group consisting of Na+, K+, Al3+, Fe2+, Fe3+, Ca2+, Mg+, NH4 + and Zn2+ . These ions can be used alone or m combination. The basic salts of this invention may also include a physiologically counter anion Qs . Such counter ions include, for example, OH , (OH) 2 2 , CH3C02 , Cl , S04 2 , P04 3 , O2 or 02 4 .
Particularly preferred basic salts of this invention include the sodium, potassium, magnesium, aluminum, calcium, ferric, ferrous, ammonium hydroxide and zinc salts of N- [N- (3 , 3 -dimethylbutyl) -1-L-α-aspartyl] -L- phenylalanme 1-methyl ester.
It is believed that the basic salts of this invention provide a number of improved properties over those of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester. In particular, the aqueous solubility is increased and the dissolution rate of the composition is greatly improved. These basic salts of neotame are sweet m taste. Thus, the basic salts of N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanme 1-methyl ester will be particularly useful m beverage systems, particularly since additional methods or mechanical preparations are diminished or not necessary
to provide for quick dissolution such as desired in a table top sweetener. The basic salts of this invention may be admixed with known bulking agents to prepare tablets, powdered and granular sweeteners using methods well known to those skilled in the art. Another advantage of the basic salts of this invention is that they do not exhibit the dusting problems associated with N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanine 1-methyl ester.
The basic salts may also be used to prepare a liquid, low-calorie sweetener by dissolving a high concentration of the basic salt of this invention in an aqueous or alcoholic system, e.g., water, propylene glycol, a water/propylene glycol mixture, ethanol or a water/ethanol mixture. Such a liquid, low-calorie sweetener may find utility in such foodstuffs as gelatin desserts, fruit flavored beverages, cereal, cake mixes, fruit juices, syrups, salad dressings, pet foods, carbonated soft drinks, table top sweeteners and the like. Such utilities are not restrictive since other applications may include cough medicines, tonics and the like. One embodiment of this invention of particular interest contemplates a liquid table top sweetener as a replacement for sucrose and other known sweeteners. The liquid low calorie sweetener generally will contain up to about 40% by weight of the basic salt of N- [N- (3, 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanine 1-methyl ester, the concentration depending, of course, on the desired end use.
The Examples which follow are intended as an illustration of certain preferred embodiments of the invention, and no limitation of the invention is implied.
Example 1
Sodium Salt of N- [N- (3, 3 -dimethylbutyl) - L-α-aspartyl] -L-phenylalanine 1-methyl ester Sodium bicarbonate (1.06 g, 0.0126 mol) was dissolved in 150 ml of water. N- [N- (3 , 3-dimethylbutyl) -L-α- aspartyl] -L-phenylalaninel-methyl ester (5.00 g, 0.0126 mol) was added and the slurry was stirred for 24 hours. The resulting clear solution was then freeze dried to yield 5.2 g of a white solid. The resulting sodium salt dissolved in water (0.1 g in 100 mL) almost instantly by visual observation and in less than 110 seconds by spectrophotometric analysis. Anal. Calcd for C20H29N2O5Na.H2O: C, 57.39 ;H, 7 : 48 ;N, 6.69. Found: C,57.65;H,7.44;N,6.75.
Example 2
Potassium Salt of N- [N- (3 , 3 -dimethylbutyl) - L-α-aspartyl] -L-phenylalanine 1-methyl ester
Potassium bicarbonate (0.51 g, 0.0050 mol) was dissolved in 50 ml of water. N- [N- (3 , 3 -dimethylbutyl ) - L-α- aspartyl] -L-phenylalanine 1-methyl ester (2.00 g, 0.0050 mol) was dissolved in acetone (50 mL) and added to the aqueous solution of potassium bicarbonate. The production of carbon dioxide gas was evident from the formation of bubbles on the walls of the flask. The solution was stirred for 1 hour and the organic solvent removed on a rotary evaporator. The resulting clear solution was freeze dried to yield 2.15 g of a white solid. The potassium salt dissolved in water (0.1 g in 100 mL) almost instantly by visual observation and in less than 60 seconds by spectrophotometric analysis. Anal. Calcd for C20H29N2O5K.H2O : C, 55.26 ;H, 7.20 ;N, 6.45. Found: C,55.28;H,7.29;N,6.62.
Example 3
Magnesium Salt of N- [N- (3 , 3 -dimethylbutyl) - L-α-aspartyl] -L-phenylalanine 1-methyl ester Magnesium hydroxide (0.147 g, 0.0025 mol) was mixed with 300 mL of water and N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanine 1-methyl ester (2.00 g, 0.0050 mol) was added and the slurry stirred. After stirring for 3 days the slurry became a clear solution. This aqueous solution was then freeze dried to yield 1.99 g of a fluffy white solid. The magnesium salt product dissolved in water (0.1 g in 100 mL) instantly (visual observation) . Anal. Calcd for C40H58N4O10Mg.5H2O : C,55.25;H,7.89;N,6.45. Found: C, 55.07 ;H, 7.64 ;N, 6.68.
Example 4
Aluminum Salt of N- [N- (3 , 3 -dimethylbutyl ) - L-α-aspartyl] -L-phenylalanine 1-methyl ester Aluminum hydroxide (0.161 g, 0.00168 mol) was mixed with water (300 mL) . N- [N- (3 , 3 -dimethylbutyl) - L-α-aspartyl] -L-phenylalanine 1-methyl ester (2.00 g, 0.0050 mol) was added and the mixture stirred for 3 days. Some solid material remained in the flask. This was removed by filtration and the clear filtrate was freeze dried to yield 2.01 g of a white solid. The aluminum salt dissolved in water (0.1 g in 100 mL) in 120 seconds (visual observation). Anal. Calcd for C60H87N6O15A1.3H2O : C, 59.39 ; H, 7.74 ;N, 6.93. Found: C, 59.93 ;H, 8.02 ;N, 7.04.
Example 5
Calcium Salt of N- [N- (3 , 3 -dimethylbutyl ) - L-α-aspartyl] -L-phenylalanine 1-methyl ester
Calcium hydroxide (0.187 g, 0.0025 mol) was mixed with water (300 mL) . N- [N- (3 , 3 -dimethylbutyl) -L-α- aspartyl] -L-phenylalanine 1-methyl ester (2.00 g, 0.0050 mol) was added and the mixture was stirred for 3 days. The insoluble solid was removed by filtration
and the clear filtrate was freeze dried to yield 1.21 g of a white solid. The resulting calcium salt dissolved in water (0.1 g in 100 mL) in approximately 5 minutes (visual observation). The calcium salt of N-[N-(3,3- dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester has high solubility in water, but it appears to form a supersaturated solution. Anal. Calcd for C40H58N4O10Ca.3H2O : C, 56.58 ;H, 7.61 ;N, 6.83. Found: C, 56.61;H, 7.52 ;N, 6.93.
Comparative Example 1
Dissolution of N- [N- (3 , 3 -dimethylbutyl) - L-α-aspartyl] -L-phenylalanine 1-methyl ester in Water
N- [N- (3 , 3 -dimethylbutyl) -L-α-aspartyl] -L-phenylalanine 1-methyl ester (0.05 - 0.1 g) was dissolved in water (100 mL) . The compound completely dissolved in 5-7 minutes (visual observation). The dissolution of 1.0 g of N- [N- (3, 3 -dimethylbutyl) -L-α-aspartyl] -L- phenylalanine 1-methyl ester in 100 mL of water required approximately 45 minutes.
Other variations and modifications of this invention will be obvious to those skilled in this art. This invention is not to be limited except as set forth in the following claims.
Claims
1. A basic salt of N- [N- (3 , 3 -dimethylbutyl) -L-╬▒- aspartyl] -L-phenylalanine 1-methyl ester represented by the formula
wherein X+ is selected from the group consisting of Na\ K\ Al3+, Fe2+, Fe3+, Ca2+, Mg2+, NH4 + and Zn2+; Q╬▓" is absent or a physiologically acceptable counter anion; and m-s=n.
2. A basic salt according to claim 1, wherein n is 1, 2 or 3.
3. A basic salt according to claim 2, wherein QA is selected from the group consisting of OH", (0H)2 2~, CH3C02-, Cl", S04 2', P04 3", 02- or 02 4"-
4. A basic salt according the claim 3 , wherein Xra+Q3" is selected from the group consisting of Mg(0H)+, A1(0H)2 + and Ca(0H)+ and n is 1.
5. A basic salt according to claim 3, wherein Xm+Q9" is selected from the group consisting of Fe202 2+ or Fe2+ and n is 2.
6. A basic salt according to claim 1, wherein Qs~ is absent, n is 1 and Xm+ is selected from the Na+, K+ or NH4
7. A liquid low-calorie sweetener composition comprising a basic salt of a dipeptide-sweetener represented by the formula wherein Xra+ is selected from the group consisting of Na\ K+, Al3+, Fe2+, Fe3\ Ca2+, Mg2+, NH4 + and Zn2+; Q9" is absent or a physiologically acceptable counter anion; and m-s=n, dissolved in a consumable solvent or solvents in a concentration up to about 40% by weight of the composition to provide a high concentration liquid low-calorie sweetener.
8. A liquid low-calorie sweetener according to claim 7, wherein the solvent is ethanol.
9. A liquid low-calorie sweetener according to claim 8, wherein Xra+Qs~ is selected from the group consisting of Mg(OH)+, Al (OH) p and Ca(0H)+ and n is 1.
10. A liquid low-calorie sweetener according to claim 8, wherein Xm+Qs~ is selected from the group consisting of Fe202 2+ and Fe2+ and n is 2.
11. A liquid low-calorie sweetener according to claim 8, wherein Qs~ is absent, n is 1 and Xm+ is selected from Na+, K+ and NH4 + .
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US5850697P | 1997-09-11 | 1997-09-11 | |
US58506P | 1997-09-11 | ||
PCT/US1998/018903 WO1999012957A1 (en) | 1997-09-11 | 1998-09-11 | BASIC SALTS OF N-[N-(3,3-DIMETHYLBUTYL)-L-α-ASPARTYL]-L-PHE NYLALANINE 1-METHYL ESTER |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1012167A1 true EP1012167A1 (en) | 2000-06-28 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP98946026A Withdrawn EP1012167A1 (en) | 1997-09-11 | 1998-09-11 | BASIC SALTS OF N- N-(3,3-DIMETHYLBUTYL)-L-$g(a)-ASPARTYL]-L-PHE NYLALANINE 1-METHYL ESTER |
Country Status (18)
Country | Link |
---|---|
US (1) | US6291004B1 (en) |
EP (1) | EP1012167A1 (en) |
CN (1) | CN1378555A (en) |
AU (1) | AU751006B2 (en) |
BG (1) | BG104322A (en) |
BR (1) | BR9812638A (en) |
CA (1) | CA2303435A1 (en) |
EE (1) | EE200000122A (en) |
HU (1) | HUP0003847A3 (en) |
ID (1) | ID27938A (en) |
IL (1) | IL134913A0 (en) |
LT (1) | LT2000028A (en) |
NO (1) | NO20001269L (en) |
PL (1) | PL339211A1 (en) |
SI (1) | SI20331A (en) |
SK (1) | SK3282000A3 (en) |
TR (1) | TR200000729T2 (en) |
WO (1) | WO1999012957A1 (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6692778B2 (en) * | 1998-06-05 | 2004-02-17 | Wm. Wrigley Jr. Company | Method of controlling release of N-substituted derivatives of aspartame in chewing gum |
EP1164872A1 (en) * | 1999-03-26 | 2002-01-02 | The NutraSweet Company | PARTICLES OF N- N-(3,3-DIMETHYLBUTYL)-L-$g(a)-ASPARTYL]-L-PHENYLALANINE 1-METHYL ESTER |
AR023208A1 (en) * | 1999-03-29 | 2002-09-04 | Nutrasweet Co | NUTRACEUTICS WITH 1-METHYL ESTER OF N- [N-3,3-DIMETILBUTIL) -L-ALFA-ASPARTIL] -L-PHENYLALANINE |
AU5127800A (en) * | 1999-05-13 | 2000-12-05 | Nutrasweet Company, The | Use of additives to modify the taste characteristics of n-neohexyl-alpha-aspartyl-l-phenylalanine methyl ester |
WO2000069282A1 (en) * | 1999-05-13 | 2000-11-23 | The Nutrasweet Company | Modification of the taste and physicochemical properties of neotame using hydrophobic acid additives |
AU1093401A (en) * | 1999-10-19 | 2001-04-30 | Nutrasweet Company, The | Pharmaceutical compositions containing n-(n-(3,3-dimethylbutyl)-1-alpha-aspartyl)-l-phenylalanine methyl ester |
US20030008047A1 (en) * | 2000-03-17 | 2003-01-09 | Schroeder Steve A. | Stability enhancement of sweeteners using salts containing divalent or trivalent cations |
US7326430B2 (en) * | 2000-07-18 | 2008-02-05 | The Nutrasweet Company | Method of preparing liquid compositions for delivery of N-[N- (3,3-dimethylbutyl-L-α-aspartyl]-L-phenylalanine 1-methyl ester in food and beverage systems |
US7923047B2 (en) * | 2006-06-30 | 2011-04-12 | Conagra Foods Rdm, Inc. | Seasoning and method for seasoning a food product while reducing dietary sodium intake |
US20110097449A1 (en) * | 2006-06-30 | 2011-04-28 | Conagra Foods Rdm, Inc. | Seasoning and method for seasoning a food product while reducing dietary sodium intake |
US20080003339A1 (en) * | 2006-06-30 | 2008-01-03 | Clinton Johnson | Seasoning and method for seasoning a food product utilizing small particle sea salt |
US20080038411A1 (en) * | 2006-06-30 | 2008-02-14 | Michael Jensen | Seasoning and method for enhancing and potentiating food flavor |
US20080008790A1 (en) * | 2006-06-30 | 2008-01-10 | Michael Jensen | Seasoned food, seasoning, and method for seasoning a food product |
NZ575995A (en) * | 2006-09-27 | 2011-03-31 | Conagra Foods Rdm Inc | Seasoning and method for enhancing and potentiating food flavor utilizing microencapsulation |
US7750631B2 (en) * | 2007-06-22 | 2010-07-06 | Morpho Detection, Inc. | Passenger inspection system and methods for using the same |
FR3102041A1 (en) | 2019-10-22 | 2021-04-23 | Aroma Sens | Sweetener for electronic cigarette liquids |
CN112321676B (en) * | 2020-12-12 | 2022-06-14 | 山东诚汇双达药业有限公司 | Salt forming method of neotame |
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US4031258A (en) | 1972-03-30 | 1977-06-21 | General Foods Corporation | Inorganic salts of dipeptide sweeteners |
CA1028197A (en) | 1973-04-02 | 1978-03-21 | Jeffrey H. Berg | Concentrated liquid low calorie sweetener |
ES8604766A1 (en) * | 1985-09-20 | 1986-03-16 | Palomo Coll Alberto | Sweetening salts |
FR2697844B1 (en) | 1992-11-12 | 1995-01-27 | Claude Nofre | New compounds derived from dipeptides or dipeptide analogues useful as sweetening agents, process for their preparation. |
FR2719590B1 (en) | 1994-05-09 | 1996-07-26 | Claude Nofre | Improved process for the preparation of a compound derived from aspartame useful as a sweetening agent. |
BE1009660A3 (en) * | 1995-10-11 | 1997-06-03 | Holland Sweetener Co | Sweetener salts. |
IT1281432B1 (en) | 1995-10-12 | 1998-02-18 | Gisulfo Baccini | PUNCHING MACHINE |
US5728862A (en) | 1997-01-29 | 1998-03-17 | The Nutrasweet Company | Method for preparing and purifying an N-alkylated aspartame derivative |
-
1998
- 1998-09-04 US US09/146,963 patent/US6291004B1/en not_active Expired - Lifetime
- 1998-09-11 WO PCT/US1998/018903 patent/WO1999012957A1/en not_active Application Discontinuation
- 1998-09-11 SK SK328-2000A patent/SK3282000A3/en unknown
- 1998-09-11 BR BR9812638-5A patent/BR9812638A/en not_active Application Discontinuation
- 1998-09-11 PL PL98339211A patent/PL339211A1/en unknown
- 1998-09-11 EP EP98946026A patent/EP1012167A1/en not_active Withdrawn
- 1998-09-11 SI SI9820063A patent/SI20331A/en unknown
- 1998-09-11 CA CA002303435A patent/CA2303435A1/en not_active Abandoned
- 1998-09-11 EE EEP200000122A patent/EE200000122A/en unknown
- 1998-09-11 CN CN98811057A patent/CN1378555A/en active Pending
- 1998-09-11 TR TR2000/00729T patent/TR200000729T2/en unknown
- 1998-09-11 AU AU93136/98A patent/AU751006B2/en not_active Ceased
- 1998-09-11 IL IL13491398A patent/IL134913A0/en unknown
- 1998-09-11 ID IDW20000472D patent/ID27938A/en unknown
- 1998-09-11 HU HU0003847A patent/HUP0003847A3/en unknown
-
2000
- 2000-03-10 NO NO20001269A patent/NO20001269L/en not_active Application Discontinuation
- 2000-04-06 LT LT2000028A patent/LT2000028A/en unknown
- 2000-04-10 BG BG104322A patent/BG104322A/en unknown
Non-Patent Citations (1)
Title |
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See references of WO9912957A1 * |
Also Published As
Publication number | Publication date |
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BG104322A (en) | 2001-02-28 |
CN1378555A (en) | 2002-11-06 |
BR9812638A (en) | 2000-08-22 |
HUP0003847A3 (en) | 2002-06-28 |
NO20001269D0 (en) | 2000-03-10 |
SK3282000A3 (en) | 2000-10-09 |
EE200000122A (en) | 2000-12-15 |
US6291004B1 (en) | 2001-09-18 |
LT2000028A (en) | 2000-12-27 |
NO20001269L (en) | 2000-05-10 |
CA2303435A1 (en) | 1999-03-18 |
PL339211A1 (en) | 2000-12-04 |
ID27938A (en) | 2001-05-03 |
TR200000729T2 (en) | 2002-01-21 |
AU751006B2 (en) | 2002-08-08 |
SI20331A (en) | 2001-02-28 |
HUP0003847A2 (en) | 2002-01-28 |
IL134913A0 (en) | 2001-05-20 |
WO1999012957A1 (en) | 1999-03-18 |
AU9313698A (en) | 1999-03-29 |
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